Title: CIR Reaches Verdicts on Butyl Myristate, HC Red No. 3 and More

The Cosmetic Ingredient Review (CIR) Expert Panel announced ingredient verdicts, including tentative safety assessments on butyl myristate, Cocos nucifera (coconut) oil, sodium cetearyl sulfate and tall oil acid, along with the approvals of HC Red No. 3 and phenyl methyl pyrazolone, among others, at its June 4, 2008, meeting. Since the CIR expert panel examines the science behind ingredients to determine their safety, the Personal Care Products Council and the US Food and Drug Administration hold these verdicts in high esteem; thus the panel's decisions weigh heavily into ensuring product safety. Following are the notes reported from the CIR June 4 meeting that can also be found on the group's Web site at: www.cir-safety.org.

Acetamide MEANo new safety test data were found for acetamide MEA. The CIR Expert Panel noted that the safety assessment of MEA itself did restrict usage to rinse-off products based on a concern about skin irritation. Acetamide MEA, however, is considered to be a stable compound and not likely to dissociate and release MEA. The available data demonstrate that acetamide MEA is safe for use in rinse-off cosmetics and in leave-on products, if the concentration is limited to 7.5%. That conclusion was confirmed.

Chlorhexidine, Chlorhexidine Dihydrochloride, Chlorhexidine Digluconate and Chlorhexidine DiacetateThe CIR Expert Panel recognized the ongoing concern regarding potential hypersensitivity reactions to chlorhexidine-impregnated medical devices. These reactions are indicative of an IgE-mediated allergic reaction and are considered serious. The concentration limits imposed in the CIR Expert Panel safety assessment on these ingredients, however, are sufficient to ensure safety of their use in cosmetics and the original conclusion was confirmed.

Methenamine The newly available safety test data regarding this preservative were consistent with those data in the original safety assessment. Methenamine functions as a formaldehyde releaser. As previously noted by the CIR Expert Panel, a fundamental equilibrium exists between these releasers and free formaldehyde itself, resulting in a steady state of availability of formaldehyde in aqueous solutions. If the level of preservative is kept low, then the level of formaldehyde will not present any safety concerns. The conclusion that methenamine is safe at concentrations up to 0.16% was confirmed. Consideration was given to adding methenammonium chloride to this safety assessment. The CIR Expert Panel determined that the chemical structure was dissimilar (methyl group added to the organic amine ring structure) and that the safety test data for methenamine could not be extrapolated to methenammonium chloride.

Quaternium-15Most recent patch-testing publications have documented that the sensitization rate for quaternium-15 in the general population has risen to almost 10%. The CIR Expert Panel determined, therefore, to reopen this safety assessment to establish a limit of 0.2% (shown to not sensitize) for the safe use of quaternium-15.

Re-review SummariesThe CIR Expert Panel approved the re-review summaries for 2-chloro-p-phenylenediamine and 2-chloro-p- phenylenediamine sulfate, HC Red No.3, phenyl methyl pyrazolone and shellac. Editorial changes to improve the flow of the conclusion statement were adopted as well as other editing to improve the flow of the presentation of information.

Reviews Scheduled for 2009Based on the current priority list, the ingredients/ingredient groups listed below are likely to be under active review in 2009. This is based on the enhancements to the CIR infrastructure as announced previously. These are in addition to the re-reviews that would normally be scheduled. If the priority list is updated, these ingredients/ingredient groups may not remain on the list. When new information is available on ingredients/ingredient groups to be considered in 2009, it will be provided.

Toluene-2,5-diamine, toluene-2,5-diamine sulfate, and toluene-3,4-diamine;1 cocamidopropyl betaine2All interested persons are provided 60 days to review and comment on the Scientific Literature Review of available safety test and related data on these ingredients. Copies of the review are/will be available from CIR (see attached order form). Comments should identify additional published data that should be included or provide unpublished data which can be made public and included. For consideration, please submit data and comments to: Dr. F. Alan Andersen, CIR Director. All submissions should be received on or before Aug. 13, 2008. Draft reports will be reviewed at the Sept. 22-23, 2008, CIR Expert Panel Meeting.

June Meeting Notes

1. Scientific Presentations

William Stott, PhD, representing the Alkanolamines Panel of the American Chemistry Council, reviewed the large body of data developed since the point 10 years ago when studies conducted by the NTP reported clear evidence that DEA and cocamide DEA were carcinogenic in male and female mice. The work has demonstrated that DEA affects mouse choline metabolism, which leads to cellular choline depletion, which leads to altered DNA methylation, which leads to altered gene expression (increased DNA synthesis and oncogene expression, reduced tumor suppressor gene expression and apotosis).

In work conducted at FDA and elsewhere, dermal penetration of DEA in personal care product vehicles was found to be significantly higher through mouse skin than either rat or human skin. In addition, the activity of choline oxidase, which is hundreds of times higher in the mouse compared to humans, suggesting that humans are resistant to choline deficiency — choline oxidase levels in the rat, however, are even higher than in the mouse. Overall, the available data support that DEA carcinogenesis in the mouse is related to choline depression and the effect is reversible and threshold-based. Given the known resistance in humans to choline deficiency, the data does not suggest a human health risk from the use of DEA and DEA fatty acids in cosmetic products.

Julie Skare, PhD, from the Procter & Gamble Company, provided an update on hair dye epidemiology, with a particular focus on the recent International Agency for Research on Cancer review (Baan et al. 2008, Carcinogenicity of some aromatic amines, organic dyes and related exposures, Lancet Oncology 9:322). She noted that the findings are not different from those in the 1993 IARC review, although there are three times as many studies of hair dye personal use and almost twice the number of hairdresser and barber occupational studies.

For occupations as a hairdresser and barber, the review group again concluded that occupational exposures are probably carcinogenic to humans, although no aspect of these occupations was identified as causal. For personal use of hair dyes, the IARC review concluded that the available epidemiology studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding a causal association between exposure and cancer. Limited animal studies can’t be interpreted as showing either the presence or absence of a carcinogenic effect. Overall, therefore, the IARC review group concluded that personal use of hair dyes was not classifiable as to its carcinogenicity in humans.

The IARC review group did specifically consider a report in press (now published) by Yawei Zhang, a member of the IARC working group (Zhang et al. 2008, Personal Use of Hair Dye and the Risk of Certain Subtypes of Non-Hodgkin Lymphoma, Am. J. Epidem. 167 (11) 1321-1331). This report presented pooled data from four previously published studies with detailed information on hair dye use. The authors reported an increased risk of Non-Hodgkin Lymphoma in women who started using hair dyes before 1980 but analysis by product type (permanent vs. non-permanent) or color (dark vs. light) were similar (when they were expected to be different — permanent > non-permanent and dark > light). The IARC working group noted that this absence of a clear pattern is an ongoing reason why the epidemiologic evidence was inadequate.

2. RIFM Interactions

Ladd Smith, PhD, Director of the Research Institute for Fragrance Materials addressed several topics in the ongoing interaction between RIFM and CIR, including dual use ingredients (ingredients that function as a fragrance and, for example, a solvent), the potential for CIR to undertake additional reviews of certain solvent groups, and the nature of the data needed to resolve the benzyl alcohol, benzoic acid and sodium benzoate insufficient data conclusion for products that may be inhaled.

The CIR Expert Panel appreciated the information that the REXPAN committee at RIFM would consider information on nonfragrance use of fragrance chemicals in its safety reviews, suggesting that there would not be a need for the CIR Panel to perform its own review to address the nonfragrance use. Ongoing sharing of information between the programs is intended to further ensure that duplicate efforts are not undertaken to address particular chemicals.

Because the use of certain solvents used in fragrances may increase as the use of others phases out, the CIR Panel encouraged RIFM and the Personal Care Products Council to work together to suggest a group of solvents used in fragrances that could be reviewed by CIR that would proactively address the expected shift in usage.

The CIR Expert Panel stated that a four-week inhalation toxicity study would be adequate to address the data insufficiencies for benzyl alcohol, bnenzoic acid and sodium benzoate use in products that may be inhaled.

3. Reports Tabled

Calendula officinalis extract, Calendula officinalis flower, Calendula officinalis flower extract, Calendula officinalis flower oil, and Calendula officinalis seed oilThe CIR Expert Panel noted that the report had been expanded to include information from applicable existing CIR safety assessments (e.g., pyrogallol) and information from RIFM safety assessments (e.g., triterpenes). Additional publications also will be included in the draft document. The panel, however, expressed several concerns about data gaps and tabled further discussion to allow interested parties the opportunity to provide such data. This data includes:

(1) Since tannins comprise 6-10% of material derived from Calendula, how much of the catechol component would be pyrocatechol? This is important because the panel previously has determined that pyrocatechol is unsafe for use in leave-on cosmetic products. (2) How much of the material derived from Calendula are quinones? The panel has restricted the concentration in cosmetics of related chemicals. (3) How much of the material derived from Calendula are coumarins? The panel is concerned about the limited evidence in animals regarding carcinogenicity.

The panel noted that, if thisdata is not available, limits on the concentration of these components may be established to assure that Calendula extracts are safe for use in cosmetics. Interested parties should use this opportunity to provide additional available unpublished data for inclusion in the draft document. The panel will review at its Sept. 22-23, 2008, meeting.

In order to create a comprehensive document containing data that will adequately document the safety of this group of chemicals, the panel tabled further discussion to allow inclusion of ammonium laureth sulfate and sodium laureth sulfate in this report. Interested parties are encouraged to provide any relevant data on these two additional ingredients. The panel will review a revised draft at its September 22-23 meeting.

4. New high priority ingredient identified - Chlorphenesin Based on ongoing concern about potential adverse effects in infants exposed to chlorphenesin that had been used in nipple creams, the FDA requested that CIR undertake a safety assessment. The CIR Expert Panel agreed to add this to the high priority list. In addition to assessing the safety of chlorphenesin in cosmetics, such a review should also address the potential use of chlorphenesin carbamate in cosmetics. Currently, chlorphenesin carbamate is considered to be a drug.

5. Ongoing re-reviews CIR staff will gather any new safety test data from the open scientific literature, FDA will provide current uses as a function of product category, and industry will conduct surveys to determine current use concentrations for the listed safety assessments and present the information to the CIR Expert Panel at the Sept. 22-23, 2008, meeting. The CIR also will prepare a table that lists other cosmetic ingredients that appear to be chemically related to the above named ingredients so that the CIR Expert Panel may determine if the safety of any additional ingredients are supported by the existing safety assessment.

Sodium dodecylbenzenesulfonate, TEA-dodecylbenzenesulfonate, and sodium decylbenzenesulfonateCIR is considering that the data in the original safety assessment of these three ingredients may support the safety of an additional ingredients: ammonium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, deadodecylbenzenesulfonate, isopropylamine dodecylbenzenesulfonate, magnesium isodecylbenzenesulfonate, mipadodecylbenzenesulfonate, potassium dodecylbenzenesulfonate, sodium tridecylbenzenesulfonate and teatridecylbenzenesulfonate, ethyl ester of PVM/MA copolymer and butyl ester of PVM/MA copolymer. The CIR is considering that the data in the original safety assessment may support the safety of calcium/sodium PVM/MA copolymer, isopropyl ester of PVM/MA, potassium ethyl ester of PVM/MA copolymer, potassium butyl ester of PVM/MA copolymer, PVM/MA copolymer, sodium ethyl ester of PVM/MA copolymer, and sodium butyl ester of PVM/MA copolymer.

Interested parties with data relevant to the safety assessment of these additional cosmetic ingredients are encouraged to provide such data by Aug. 3, 2008. In considering the addition of other chemicals, the safety of which may be addressed by the original safety assessment, the CIR Expert Panel has indicated that the phrase “chemically related” could include inorganic salts and simple esters.

The Panel also stated that it would consider the types of products in which any additional cosmetic ingredients are used and the concentrations at which they are used.

References1. This safety assessment was reopened in December 2007 because of concerns about the limited genotoxicity data and the absence of carcinogenicity data for toluene-3,4-diamine. At that time, the expert panel considers that the available data are insufficient to support the safety of this ingredient. Data needed for toluene-3,4-diamine included mammalian genotoxicity data. If positive, a two-year dermal carcinogenicity study using NTP methods may be needed. Concentration of use and dermal penetration data also would be useful. Any data received will be included in the SLR.

2. This safety assessment was re-opened in April 2007 based on safety concerns that relate to the sensitization potential of this ingredient in both leave-on and rinse-off products. The expert panel acknowledged that the sensitization potential of this ingredient likely relates to the presence of two impurities that have allergenic potential: amidoamine and 3-dimethylaminopropylamine [DMAPA] . The expert panel also noted new uses of this ingredient in sprays and powders that could be inhaled but that data was available suggesting that, in general, cosmetic product sprays do not produce respirable particle sizes.

Data needed to include: 1) the levels of amidoamine and DMAPA impurities that reasonably can be achieved in the cocamidopropyl betaine manufacturing process; 2) additional sensitization data for DMAPA and amidoamine, if available; and 3) inhalation toxicity data for cocamidopropyl betaine, in the new use formulations such as sprays and powders, or updated information on particle size in cosmetic sprays, if available.